title: Chloride extrusion enhancers as novel therapeutics for neurological diseases.
abstract: The K(+)-Cl(-) cotransporter KCC2 is responsible for maintaining low Cl(-) concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABA(A) and glycine receptors. Although no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favored therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl(-) transport. We designed an assay for high-throughput screening that led to the identification of KCC2 activators that reduce intracellular chloride concentration ([Cl(-)]i). Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl(-)]i. CLP257 restored impaired Cl(-) transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalized stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.
authors.affiliation: 1] Institut Universitaire en Santé Mentale de Québec, Québec, Québec, Canada. [2] Department of Psychiatry & Neuroscience, Université Laval, Québec, Québec, Canada. [3] Chlorion Pharma, Laval, Québec, Canada. [4].
authors.forename: Martin
authors.initials: M
authors.lastname: Gagnon
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Bergeron
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lavertu
authors.forename: Annie
authors.initials: A
authors.lastname: Castonguay
authors.forename: Sasmita
authors.initials: S
authors.lastname: Tripathy
authors.forename: Robert P
authors.initials: RP
authors.lastname: Bonin
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez-Sanchez
authors.forename: Dominic
authors.initials: D
authors.lastname: Boudreau
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Lionel
authors.initials: L
authors.lastname: Dumas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Valade
authors.forename: Karine
authors.initials: K
authors.lastname: Bachand
authors.forename: Mariève
authors.initials: M
authors.lastname: Jacob-Wagner
authors.forename: Christian
authors.initials: C
authors.lastname: Tardif
authors.forename: Irenej
authors.initials: I
authors.lastname: Kianicka
authors.forename: Paul
authors.initials: P
authors.lastname: Isenring
authors.forename: Giorgio
authors.initials: G
authors.lastname: Attardo
authors.forename: Jeffrey A M
authors.initials: JA
authors.lastname: Coull
authors.forename: Yves
authors.identifier: 0000000257799330
authors.initials: Y
authors.lastname: De Koninck
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D002712:Chlorides / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000819:agonists*; D053778:Thiazolidines / Q000737:chemistry / Q000627:therapeutic use*; D000096922:K Cl- Cotransporters
chemical_list: D000700:Analgesics; D002712:Chlorides; D027981:Symporters; D053778:Thiazolidines; D000096922:K Cl- Cotransporters; C585828:CLP257